ReviewEpigenetics: The link between nature and nurture
Introduction
Epigenetics is the field of study surrounding stable alterations to the DNA and histone proteins that alter gene expression (Jaenisch and Bird, 2003). Epigenetic modifications are responsible for tightly regulated tissue and cell-type specific gene expression patterns. Aberrations in these expression patterns can give rise to certain diseases, most notably some types of cancer (Esteller, 2008). Interestingly, certain environmental factors can influence the expression of genes within a cell without mutations to the genome, but instead through modifying epigenetic marks. These environmental changes to the epigenome are so robust that even monozygotic twins can be identified by analyzing their unique epigenetic patterns (Fraga et al., 2005). Changes in epigenetic patterns can result in an alteration of gene expression, which in itself can have many downstream effects including changes in disease risk, stress response and metabolism (Lillycrop et al., 2005, Liu et al., 1997, McGowan et al., 2009). Epigenetics is the broad term used to describe a variety of reversible modifications to the genome that are meiotically and mitotically heritable, although the requirement for a modification to heritable has been contested.
Epigenetic programming may begin while the fetus is developing in the uterus. Maternal environmental exposures during gestation are one important area of epigenetic research, but the gametes of the offspring might also be affected by those environmental factors while in the uterus, leading some to believe that our grandmother’s environment might be affecting our own gene transcription through epigenetic mechanisms (Cropley et al., 2006). Furthermore, it is suggested that preconceptional paternal exposure to environmental factors can determine the offspring’s phenotype epigenetically (Puri et al., 2010). Several changes to the genome fall into the category of epigenetics, including DNA methylation, histone modifications, chromatin remodeling and miRNA, although it is still debated if miRNA can be categorized as an epigenetic phenomenon. In this review we included miRNA, because of the ability miRNA has in affecting epigenetic phenomena, as well as the ability of epigenetic phenomena to change expression of miRNA. Taken together, these epigenetic mechanisms can provide the link between environmental factors and phenotypical changes during the whole lifetime of an organism (Fig. 1).
Section snippets
Functions of DNA methylation
DNA methylation is perhaps the most well studied epigenetic mark. Methylation of the 5′ position of a cytosine within the genome occurs by the enzymatic family of DNA methyltransferases (DNMTs), thereby forming 5-methylcytosine (5-mC). S-Adenosylmethionine (SAM), a modified amino acid produced in the one-carbon metabolism pathway, donates the methyl group in this reaction (Niculescu and Zeisel, 2002). 5-Methylcytosine, often times called the “fifth-base”, is present in an estimated 4–6% of the
Hydroxymethylation as an intermediate in demethylation
Recently a new epigenetic mark called 5-hydroxymethylcytosine has been proposed as a player in the removal of methyl groups from cytosine bases. Hydroxymethylcytosine (or 5-hmC) has been referred to as the “sixth-base” because of its potential regulatory role in gene transcription similar to 5-mC (Münzel et al., 2011). Less than 1% of cytosines are hydroxylated in mammalian DNA, and the level varies by tissue with the central nervous system having the highest amount (Globisch et al., 2010).
Compacting the DNA
DNA is compacted by tightly weaving approximately 147 base pairs around proteins called histones, forming a DNA-protein complex called a nucleosome. Each nucleosome consists of an octamer of two copies of four core histones: H2A, H2B, H3 and H4. Various post-translational modifications to the N-terminal histone tails can occur in mammalian cells, including histone acetylation, methylation, phosphorylation, ubiquitination, ADP-ribosylation and biotinylation. These modifications result in a
Mechanisms for chromatin remodeling
Regulation of gene transcription can also occur at the chromatin level. Through tightly packing the flexible euchromatin into nucleosome-rich heterochromatin, transcription factors and RNA polymerases can no longer transcribe regions of DNA and that gene becomes silenced. This compacted chromatin will form both to stabilize the genome (at the centromere and telomeres of a chromosome for example) and to prevent transcription of a specific target gene. The mechanism by which chromatin are
Mechanism of action
A relatively new area of epigenetic research focuses around a form of small non-coding RNAs that are usually about 20 to 30 nucleotides in length called miRNAs. Unlike the ncRNAs discussed in section 5.4 above, the primary mechanism by which miRNAs act to post-transcriptionally silence target genes is by recognizing target sequences in the mRNA by Watson-Crick base pairing of nucleotides 2 through 8 in the miRNA, called the seed region. The miRNA can inhibit translation of mRNA either by
Nutritional epigenetics
Certain dietary bioactive food components can change gene expression via alterations in DNA methylation and histone modifications, a field of study that may one day lead to the development of the “epigenetic diet” (Hardy and Tollefsbol, 2011, Park et al., 2011). The availability of the universal methyl donor, SAM, is determined by one-carbon metabolism, a pathway involving vitamins B6, B12, folate, betaine and choline along with the amino acids methionine, cysteine, serine and glycine. When a
Conclusion and future perspectives
The field of epigenetics is rapidly evolving to contain many types of modifications to the genome that do not alter the genetic sequence itself. As research continues, the mechanism of action for each of these epigenetic modifications is further elucidated. An interesting aspect of epigenetics is the interaction between the genome and the environment, a research area that is bettering our understanding of how the environment shapes our own phenotype along with the phenotype of our offspring,
Acknowledgments
This material is based upon work supported by the US Department of Agriculture, under Agreement No. 51000-074-01S. Any opinions, findings, conclusion, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the US Dept of Agriculture. This project has been supported in part by the National Institute of Health Grants R01 AG025834 (S.W.C.). Authors do not have any conflict of interest.
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Address: University of Verona, School of Medicine, Policlinic “G.B. Rossi”, P.le L.A. Scuro 10, 37134 Verona, Italy.